Interstitial cystitis (IC) is a chronic lower urinary tract disorder characterized by urinary frequency, urgency, suprapubic pressure and pain. Although various pathological mechanisms have been proposed to account for IC, the etiology of the disorder is unknown. Nevertheless, it seems reasonable to speculate that IC is an abnormality of visceral sensation and that the IC patient is either more sensitive to relatively normal afferent activity generated in the bladder or that the bladder generates abnormal afferent signals in response to an unidentified peripheral pathology. The experiments in this proposal are designed to analyze the neural pathways transmitting nociceptive information from the bladder in rats and to evaluate the influence of noxious bladder stimuli on the properties of peripheral afferent neurons and spinal neurons that process sensory input from the lower urinary tract. Several hypotheses will be tested: (1) bladder pain is triggered by normally silent (sleeping) C-fiber afferents that are sensitized by chemical mediators released at sites of inflammation or tissue injury, (2) silent C-fibers are quiescent or insensitive to mechanical stimuli such as bladder distension due to a high threshold for activation of sodium currents as well as a low threshold for activation of a potassium current which tends to decrease cell excitability, (3) inflammatory and pain producing substances sensitize bladder afferents by blocking potassium channels, (4) chronic inflammation in the bladder can alter the properties of bladder afferents to increase their excitability and alter their chemistry, (5) interactions between sympathetic efferent pathways and afferent pathways can modulate sensory input from the bladder and may be a mechanism for sensitization of silent c-fibers, (6) allodynia, defined as a painful response to a normally nonpainful stimulus, can occur in the inflamed bladder as in other organs and may be mediated by both central and peripheral mechanisms. The long term objectives of this research program are to understand the mechanisms by which irritating or tissue injuring stimuli in the lower urinary tract are detected and processed by the nervous system and in turn modulate urinary tract function. The study will utilize a multidisciplinary approach encompassing neurochemistry, electrophysiology and pharmacology.